On April 21, 2021, the track management announced that due to the COVID-19 pandemic, the event would be held with a limit of 135,000 spectators, approximately 40% capacity.

[2] The previous year's race was postponed from May 24 to August 23, then ultimately held without spectators, as was the GMR Grand Prix (which was moved to July 4).

He had to make a stop for emergency service, but the crew could not refire the stalled engine before he fell a lap down, and essentially out of contention.

Castroneves joined Hall of Fame drivers A. J. Foyt, Al Unser Sr. and Rick Mears as four-time winners.

On January 31, 2019, it was announced that the online financial services company Gainbridge would become the new presenting sponsor of the 500 under a four-year deal.

A doubleheader weekend at Texas saw Scott Dixon and first-time victor Pato O'Ward as race winners.

The GMR Grand Prix kicked off the month of May at Indianapolis on May 15, won by Rinus VeeKay, the third first-time winner of the season.

[7] The Indianapolis 500 returned to its traditional Memorial Day weekend date after being delayed to August 23 in 2020 due to the COVID-19 pandemic.

The Freedom 100, however, was not held as the 2021 Indy Lights season only included a race on the road course during GMR Grand Prix weekend.

An offseason test was scheduled at the Indianapolis Motor Speedway during the last week of October after the conclusion of the 2020 season.

[11] On Wednesday, October 28, Takuma Sato (Rahal) and Josef Newgarden (Penske) conducted test runs utilizing new aerodynamic pieces and configurations.

[13] On Friday, October 30, Sato and Newgarden were joined by Ryan Hunter-Reay (Andretti), Ed Carpenter (ECR), Pato O’Ward (Arrow McLaren SP), and Scott Dixon (Ganassi).

The series oversaw test runs to attempt to replicate the effects of racing with KERS, which will be part of the new hybrid engine package scheduled to debut in 2023.

The drivers and teams involved were Scott Dixon (Ganassi), Josef Newgarden (Penske), Alexander Rossi (Andretti), and Pato O’Ward (Arrow McLaren SP).

If any adjustments were made, or if any engine cooling efforts were performed, the car was automatically withdrawn and was required to make a new attempt.

Sage Karam was the fastest of those in the Last Row Shootout, turning a four-lap average at 229.156 mph (368.791 km/h), to secure 31st starting position.

Rinus VeeKay improved from his fifth-placed result in Saturday qualifying to take the outside of the front row, running at 231.511 mph (372.581 km/h).

The race began with Scott Dixon pulling into the lead, but by the end of the first lap, Colton Herta had overtaken him.

Ed Carpenter lost significant time when his car fell off its air-jacks and then stalled, dropping him down the order.

The worst affected were pre-race favorites Dixon and Alexander Rossi, who both ran out of fuel entering pit lane.

[42] Due to the number of cars taking penalties for stopping for emergency service, the caution period lasted 11 laps while IndyCar officials determined the running order.

At the halfway mark of the race, the running order was Daly, VeeKay, O'Ward, Ryan Hunter-Reay, and Herta.

[45] After a reshuffling of positions from pit stops and the caution, Álex Palou now held the lead ahead of Hélio Castroneves, Patricio O'Ward, and Rinus VeeKay.

Further back, Simona de Silvestro spun and damaged her car entering pit lane, forcing her to retire from the race.

Despite encountering a large pack of backmarkers on the final lap, Castroneves held off Palou to take victory.

[54] The 2021 race was the final "500" for Robin Miller, who had covered the event for roughly fifty years at The Indianapolis Star, Racer, and on television through ESPN, Speed, and NBC.

The chief announcer or "Voice of the 500" for the sixth consecutive year was Mark Jaynes with Davey Hamilton as driver analyst.

Recently retired Donald Davidson returned to the booth in a live capacity for the first time since 2019 as in 2020 due to the COVID-19 pandemic all of his appearances were taped.

Speedway historian Donald Davidson retired at the end of 2020, and his longtime program The Talk of Gasoline Alley was no longer aired.

In its place, a new Indianapolis 500 themed program title Beyond The Bricks was hosted by Jake Query (an IndyCar Radio Network veteran) and former WIBC personality Mike Thomson.